The present invention relates to novel 2,3-disubstituted-2,3-dihydro-5-hydroxybenzofurans as anti-inflammatory agents, as well as, the synthetic routes to these compounds.
Several patents have been issued on related structural types, which are stated to have similar utility, as anti-inflammatory agents are listed as follows: substituted cinnamyl-2,3-dihydrobenzofurans (Chang et al., U.S. Pat. Nos. 4,537,903 and 4,686,235), 5-hydroxy-2,3-dihydrobenzofurans (Chang, et al., U.S. Pat. No. 4,563,476), substituted phenyl-2,3-dihydrobenzofurans (Chang et al., U.S. Pat. No. 4,713,393), phenylthiomethyl-6-hydroxy-2,3-dihydrobenzopyrans (Thompson, et al., U.S. Pat. No. 4,558,067) and benzofuran-2-carboxylic acid esters (Atkinson, et al. U.S. Pat. Nos. 4,663,347 and 4,745,127).
The invention hereto describes inhibitors which contain novel substitution patterns designed to enhance the binding to 5-lipoxygenase. None of the above mentioned compounds are among the ones claimed in this patent application.
The 5-lipoxygenase enzyme controls the metabolism of arachidonic acid to the class of compounds known as leukotrienes. Inhibition of 5-lipoxygenase enzyme therefore prevents the formation of leukotrienes and so or diminishes the adverse effects of these mediators in a mammalian subject.
The leukotrienes are a novel group of biologically active mediators derived from arachidonic acid through the action of the 5-lipoxygenase enzyme system. The leukotrienes play an important role in inducing allergic reactions, such as asthma, allergic bronchitis or allergic rhinitis in man.
There are two groups of leukotrienes derived from a common unstable precursor, Leukotriene A.sub.4. The first of these are the peptido-lipid leukotrienes, the most important being leukotrienes C.sub.4 and D.sub.4. These compounds collectively account for the biologically active materials known as the slow reacting substances of anaphylaxis. They are potent in producing bronchoconstriction, increasing vascular permeability in the skin and in promoting mucous production.
The most important compound in the second group of leukotrienes is Leukotriene B.sub.4, a dihydroxy fatty acid derived from Leukotriene A.sub.4. LTB.sub.4 stimulates leukocytes formation (chemotaxis and chemokinesis) induces an increase in capillary permeability and causes smooth muscle contractions, Leukotriene B.sub.4 has chemotactic potency for macrophage and neutrophils at concentrations of 1 ng/mls. Both groups of leukotrienes are formed following oxygenation of arachidonic acid through the action of the 5-lipoxygenase enzyme. See D. M. Bailey et al., Ann. Rpts. Med. Chem. 17:203 (1982).
Leukotrienes can also mediate other disease states, these include psoriasis, atopic dermatitis, gouty arthritis and gall bladder spasms. They also may play a role in cardiovascular disease because Leukotrienes C.sub.4 and D.sub.4 act as coronary and cerebral arterial vasoconstrictors and these compounds may also have negative ionotropic effects on the myocardium. In addition, the leukotrienes are important mediators of inflammatory diseases through their ability to modulate leukocyte and lymphocyte function. See B. Samuelsson, Science 220: 568 (1983).
Finally, the invention provides novel compounds with the general structure shown in Formula I that act as inhibitors of the mammalian 5-lipoxygenase enzyme system, thus preventing the biosynthesis of the leukotrienes B.sub.4, C.sub.4, D.sub.4 and E.sub.4.